Cocaine addiction is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Given the extensive literature implicating the mesolimbic dopamine (DA) system in the reinforcing effects of cocaine, drugs designed to treat cocaine addiction have often targeted DA systems. Unfortunately, DA-based therapeutics are often ineffective or intolerable and may have abuse potential themselves. The hypocretins/orexins (HCRT) are neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Recently, the HCRT system has also been shown to influence cocaine reinforcement via actions in the DA-rich ventral tegmental area. For example, we have shown that disrupting HCRT neurotransmission within the ventral tegmental area reduces the reinforcing effects of cocaine and attenuates cocaine-induced elevations in DA within the nucleus accumbens. Based on these and other observations, we hypothesize that the HCRT system exerts a permissive, excitatory influence that enhances DA tone and ultimately supports cocaine self-administration. Thus, when HCRT signaling is disrupted, excitatory influences on DA activity are diminished and cocaine self-administration is reduced. To further characterize the extent to which the HCRT system regulates DA signaling and cocaine reinforcement, the proposed research will employ a multidisciplinary approach using sophisticated behavioral, neurochemical, and virus-mediated gene manipulation techniques. Studies will examine: 1) the extent to which HCRT signaling at HCRT 1 receptors contributes to the regulation of DA signaling in the nucleus accumbens under baseline, non- drug conditions; 2) the critical issue of whether alterations in cocaine self-administration following HCRT antagonists are associated with increased sedation; 3) the extent to which HCRT signaling alters cue-evoked and spontaneous DA signaling during cocaine self-administration; and 4) determine which HCRT receptor- expressing neurons in the ventral tegmental area (DA vs. GABA) are involved in the regulation of DA signaling and behavioral responses to cocaine using virus-mediated knockdown of HCRT receptors. Completion of this work will provide information on the degree to which pharmacological and genetic HCRT manipulations alter DA signaling under baseline conditions and in response to cocaine and the extent to which these actions affect the reinforcing effects of cocaine. Additionally, these studie will offer insight into the neural mechanisms underlying the addiction process and may provide the basis for a novel pharmacotherapy to treat cocaine addiction.